SUMMARY R21 Bold Initiative Optical pacing using graphene-cardiomyocyte interfaces for precision medicine and drug discovery The ability to produce cardiomyocytes from induced pluripotent stem cells (iPSCs) derived from patients with heart disease creates the unprecedented opportunity to decipher disease mechanisms, predict patient drug responses and develop new drugs that was unimaginable even a few years ago. This is particularly relevant for cardiac rhythm disorders, which cause half of all heart failure deaths and for which clinically relevant phenotypes have been recapitulated by iPSC-cardiomyocyte models. The heart is an electrically excitable tissue; thus, to take full advantage of iPSC-cardiomyocytes, it is imperative to electrically stimulate them to evoke clinically relevant phenotypes and monitor drug effects. Current technologies are either too cumbersome or expensive for widespread use in high throughput applications. Therefore, this proposal is to develop a graphene-based nanotechnology to optically stimulate three-dimensional Engineered Heart Tissues (EHTs) that will be inexpensive and readily implemented in screening and drug discovery settings. Our goal is to develop a new technology that would be: 1) inexpensive, 2) can be adopted in conventional cell culture dishes, 3) does not disrupt the integrity of the cell membrane and ion currents, and 4) does not require genetic manipulation of the cells. We will test the ability of the prototype nanotechnology + EHT platform to measure characteristic responses of benchmark drugs, and to discern disease specific responses using iPSC-cardiomyocytes from patients with normal and rhythm disorders. We will establish a general means of stimulation concomitant with optical recording of physiological parameters. The solution will be broadly applicable to other excitable cells, such as neurons and endocrine cells.